AU667129B2 - Injectable mesna solutions - Google Patents

Abstract

Storage-stable mesna injection solutions with a pH above 7.5 and a preparation process are described.

Description

I A Injectable Mesna Solutions Description The chemical name of the active substance mesna is sodium-2-mercaptoethane sulfonate. (Formula I) S" HS-CH 2

-CH

2

-SO

3 Na Formula I Mesna for example protects the urinary organs in the treatment of tumour diseases with ifosfamide. In addition, mesna has already been used for a long time as a mucolytic agent.

Mesna is a white hygroscopic powder with a characteristic odour.

0 The substance is highly sensitive to oxidation and rapidly decomposes on contact with oxygen to form dimesna, particularly in a humid atmosphere. (Formula II) NaSO 3

-CH

2

-CH

2

-S-S-CH

2

-CH

2 -SO3Na Formula II Mesna has hitherto been applied orally, parenterally and by 1 means of inhalation. All the dosage forms used are liquid formulations that are given in the form of ampoules or drinkable ampoules. Since mesna is very sensitive to oxidation and reacts in the presence of oxygen to form dimesna, which is poorly absorbed, the aqueous solution has to be protected against oxygen. For this purpose the solution is sealed into glass ampoules.

The solution for parenteral application is offered in 2 ml, 4 ml and 10 ml ampoules containing 10 mesna.

Mesna is used to prevent urotoxic symptoms during ifosfamide therapy.

2 Mesna is generally given simultaneously with ifosfamide as well as after 4 and after 8 hours, in each case in a dose that corresponds to 20% of the ifosfamide dose, applied intravenously. The ifosfamide dose can be between lg/m 2 to 8g/m 2 body surface. The corresponding mesna doses consequently lie within a very broad spectrum. There was therefore a desire for multi-dose containers from which any quantity of injectable solution could be withdrawn and no wastage, such as incurred with opened ampoules, occurred.

These injection bottles were also intended to contain a larger volume of solution.

Deutsches Arzheibuch 9 (German Drug Book) requires that multi-dose containers be preserved to provide protection against microbial contamination. The injectable solution filled into ampoules is very stable. This formulation was therefore used and only one preservative, namely benzyl alcohol, used throughout the world for parenterally applied aqueous systems, was added thereto. The pH value of this solution is adjusted to 6.5 with sodium hydroxide solution. The solution also contains a complexing agent since mesna forms coloured complexes with heavy metal ions.

Stability storage tests showed, however, that these solutions were partially unstable.

The degradation product was identified as mesna acetal with benzaldehyde (Formula

III)

CH\ Formula III

/S-CH

2

-CH

2

-SO

3 Na *Benzaldehyde occurs in the formulation through oxidation of the benzyl alcohol used 20 as preservative.

:It has now surprisingly been found that this degradation product is only formed at S• pH values 7.5 and is not formed at a pH value of 7.5 According to a first embodiment of this invention there is provided an injectable mesna solution with a pH value of above 7.5 comprising mesna, one or more complexing 25 agents and one or more alkaline substances, and further comprising a preservative.

Included within this invention is the use of the injectable mesna solution according to the first embodiment for the prenaration of a medicament for preventing urotoxic side effects of oxazaphosphorin treatment.

Oxazaphosphorin is a generic term for a class of substances with cytostatic acting 30 alkylating agents. Belonging to it for instance are Ifosfamide, Trofosfamide and cyclophosphamid. The urotoxicity is caused by metabolic developed Acrolein that is a characteristic feature of this group of substances.

According to a another embodiment of this invention there is provided a method for preventing the side effect of oxazaphosphorin comprising administering to a patient who has taken oxazaphosphorin an effective amount of a stable injectable pharmaceutical composition with a pH value greater than 7.5, said composition comprising mesna, one or Smore complexing agents and one or more alkaline substances.

[N:\LIBFF]00282;SAK 3 The invention thus relates to an injectable solution which contains, to 1 part of mesna for example 0.00002 2.0 parts by weight preferably 0.0001 1.0 parts by weight in particular 0.0002 0.7 parts by weight of NaEDTA as complexing agent and for example 0.0002 2.0 parts by weight preferably 0.0003 1.7 parts by weight in particular 0.0004 1.4 parts by weight to of sodium hydroxide for pH adjustment and for example 0.001 30.0 parts by weight preferably 0.01 20.0 parts by weight in particular 0.018 12.0 parts by weight of benzyl alcohol as preservative.

i The amount by weight of mesna in an injectable solution of this type is generally 1 mg per ml to 540 mg/ml. The solutions can be applied directly i.v. or designed as infusion solutions or concentrates as supplements to infusions.

The appropriate volumes are between 0.5 ml and 100 ml. Water for injection purposes is used as solvent.

*999 999 9 .99.

9 ft* '*"*Jis In addition to the possible to use: complexing agents: above listed auxiliary substances it is also for example the calcium disodium salt of edetic acid, citric acid, tartaric acid or salts of orthophosphoric acid.

for example suitable to adjust the pH: sodium hydroxide, potassium hydroxide, tromethamine, sodium acetate, trisodium citrate, sodium monohydrogen phosphate, potassium monohydrogen phosphate.

The following are Preservatives: for example p-hydroxybenzoic acid ester, m-cresol, organomercuric compounds, chlorobutanol, quaternary ammonium compounds.

The preservatives may also be used in combination with benzyl alcohol.

To prepare the solution 80-90%, preferably 85% of the requisite amount of water (lacking in oxygen, i.e. the water may contain a maximum of 1.5ppm oxygen at 20°C) are prepared and sodium edetate, benzyl alcohol and mesna dissolved with stirring and constant nitrogen gassing. When dissolution is complete the pH is adjusted to 8.0 by adding 10N sodium hydroxide solution. This solution is made up to the final volume with water (lacking in oxygen).

The solution obtained in this manner is sterilised by filtration through conventional 15 pathogen-proof filters and then filled into appropriate containers for injectable preparations. The solution is covered with nitrogen during and after filtration. The storage time until filling into the injection containers, including the time to prepare the solution, should not exceed 4-5 hours.

For sterilisation purposes, conventional pathogen-proof filters, for example conventional bacteria filters with a pore size of 0.2 utm are used. The glass vessels used are previously sterilised in conventional manner. The injection water used must be sterile and pyrogen-free and meet the requirements of the Deutsches Arzneibuch 10, 1991 edition. The injection vessels used are appropriately those made of tubular glass or blowmoulded glass of hydrolytic class II (for example 10R, 30R, 50H), see in this connection Deutsches Arzneibuch 10, 1991 edition, VI.2.1. and DIN standards 58366 part 1 and part In addition, the injection vessels as well as additional C. o [N:\LIBxx]00776:KEH ill I r| 5 auxiliary substances, such as rubber stoppers and crimped caps, should meet the requirements of DIN standards 58366, part 2 and part 3, as well as 58367, part 1.

The volume of solution in the appropriate containers amounts per s container to between 4 ml and 100 ml, preferably between 10 ml and 75 ml, in particular between 40 ml and 60 ml. The amount of mesna per glass vessel is for example 4 mg to 50 g, preferably 1 g to 7.5 g, in particular 4 g 6 g.

After filling the solution under aseptic conditions, the bottles /0 are gassed with nitrogen to expel the oxygen and closed with injection stoppers. The filled injection bottles are sterilised in a steam steriliser.

The following examples illustrate the invention: Example 1 Injection bottle with 50 ml of a 10 injectable mesna solution Composition mesna (INN) 5000.0 mg benzyl alcohol 520.0 mg sodium edetate 12.5 mg sodium hydroxide 10.0 70.0 mg 1 2) Water for injection purposes 50.0 ml approx. 52.5 g- 1) Used to adjust the pH value and is therefore variable 2) Used as 10N sodium hydroxide solution 25-175 x 10 3 ml 3) 3) The use of more or less is balanced by water for injection purposes The density of the solution is 1.05 g/ml.

Preparation of the solution of the amount of water for injection purposes (lacking in oxygen) 6 are filled into a suitable vessel and the appropriate amounts of sodium edetate, benzyl alcohol and me:na dissolved therein with stirring and constant nitrogen gassing. The solution is adjusted.

to a pH value of 8.0 by addition of 10N sodium hydroxide solution and the result made up to the final volume with water for injection purposes (lacking in oxygen).

The water for injection purposes may contain a maximum of ppm oxygen at 20 0 C. pH value, density and refractive index (n 20 1.34-1.36) are determined as in-process controls.

1o The solution is sterilised by filtration using a 0.2 pm membrane filter. The solution is covered with nitrogen during and after filtration. A Sartorius SM 11107 or SM 11307 or Pall Filter NRP is, for example, used as a conventional pathogen-proof filter.

Particular and bacterial contamination is avoided during storage of the solution before filling. Storage at room temperature (200 22 0 C) should not exceed 4-5 hours. Additional conventional prefilters may also be used for purposes of sterile filtration (for example Sartorius SM 13400 or Pall LPA) to protect the S sterile filter.

R0 Cleaning the injection bottles DIN 50H/II, colourless 50 ml injection bottles are used as containers. They are flushed with hot and cold demineralised water and with air. All cleaning media are filtered to free them of suspended matter. To prevent recontamination due to particles from the air, the bottles are dried and sterilised using hot air (discontinuously at 180°C, 2 hours, continuous at 350 0 C for minutes).

The rubber stoppers (for example Helvoet FM 157/1 grey) used tc close the injection bottles are cleaned using demineralised 0o water and, for example, a cleaning agent consisting of non-ionogenic surfactants and phosphoric acid esters in aqueou-s solution (for example MB 70, Huber, Freiburg).

The cleaned stoppers are rinsed free of fibres and fluff using water for injection purposes or filtered demineralised water.

k It 7 The stoppers cleaned in this manner are then sterilised using steam.

The injection bottles cleaned and sterilised in this manner are then gassed aseptically with nitrogen to displace the oxygen in T the air, filled with 52 ml mesna solution and gassed again.

Finally, the stoppers are positioned and secured with crimped caps. The filling volume is statistically monitored by then weighing the contents. The nominal filling amount is 52 ml 54.6 g. The residual oxygen content in the headspace of the /0 injection bottle is also monitored.

The filled injection bottles are sterilised in a steam steriliser (at least 1200 20 minutes).

The injection bottles are checked for incorrect closure, outer faults, clarity and particulate impurities.

*0 /6 Example 2 0 Injection bottle with 50 ml of a 50 concentrate for addition to infusion solutions: Composition: mesna 25,000 g benzyl alcohol 0.520 g Na EDTA 0.0125 g sodium hydroxide 0.05 0.35 g water for injection purposes ad 50,000 ml 61.0 g 0 The density of the concentrate is 1.22 g/ml 20 0 C. The preparation and sterile filtration of the solution, cleaning and neo.

sterilisation of the bottles and rubber stoppers, filling, closing of the bottles and final sterilisation are carried out according to Example 1.

Claims (4)

1. A stable, injectable pharmaceutical composition with a pH value of above comprising mesna, one or more complexing agents and one or more alkaline substances and further comprising a preservative.

2. The composition of claim 1 wherein the pH is 7.5 to

3. A stable, injectable pharmaceutical composition substantially as hereinbefore described with reference to any one of the Examples.

4. A method for preventing the side effect of oxazaphosphorin comprising administering to a patient who has taken oxazaphosphorin an effective amount of a stable injectable pharmaceutical composition with a pH value greater than 7.5, said composition comprising mesna, one or more complexing agents and one or more alkaline substances. Dated 10 January, 1996 ASTA Medica Aktiengesellschaft Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON .o g S* a ea a e a *o*oo o *eo [N:\LIBFF]00282:SAK Injectable Mesna Solutions Abstract The invention provides storage-stable injectable solutions of mesna, sodium-2- mercaptoethane sulfonate of the formula HS-CH1 2 -CH 2 -SO 3 Na Formula I. The solutions have a pH value higher than 7.5. They are useful for preventing the side effect of oxazaphosphorin. IN:'L11U101457:GA